|Mutation Type||splice site (4 bp from exon)|
|Coordinate||71,686,976 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||Janus kinase 3|
|Chromosomal Location||71,676,296-71,690,575 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a knock-out allele exhibit impaired B cell development, small thymi and T cell proliferate. Point mutation homozygotes develop autoimmune inflammatory bowel disease, decreased susceptibility to malaria infection and/or increased susceptibility to bacterial infection. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000060073] [ENSMUSP00000105639] [ENSMUSP00000105640]|
|Predicted Effect||probably benign|
|Predicted Effect||probably benign|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.0898|
|Is this an essential gene?||Possibly essential (E-score: 0.721)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.727; ML prob: 0.674; human score: 2.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:48 PM by Diantha La Vine|
|Record Created||2014-06-14 10:20 PM by Ming Zeng|
The citron phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R0531, some of which showed an increase in the B:T cell ratio (Figure 1) due to an increased frequency of B cells (Figure 2) as well as an increased frequency of IgM+ B cells (Figure 3) and a higher percentage of IgD+ B cells (Figure 4), all in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 74 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Jak3: a C to T transition at base pair 71,686,976 (v38) on chromosome 8, or base pair 10,594 in the GenBank genomic region NC_000074 encoding Jak3. The strongest association was found with a recessive model of linkage to the normalized B cell frequency, wherein three variant homozygotes departed phenotypically from six homozygous reference mice and 11 heterozygous mice with a P value of 2.244 x 10-7 (Figure 5). The mutation is located within the donor splice site of intron 22, four nucleotides from the previous exon. Two Jak3 protein-coding transcripts are displayed on Ensembl; both transcripts encode the same protein. The effect of the mutation at the cDNA and protein level is unknown. One possibility, shown below, is that aberrant splicing would cause skipping of the 118 base pair exon 22 (out of 25 total exons; exon 22 encodes amino acids 990-1028) and a frame-shift that results in coding of two aberrant amino acids followed by a premature stop codon in exon 23.
Genomic numbering corresponds to NC_000074. The donor splice site of intron 22, which is destroyed by the mutation, is indicated in blue; the mutated nucleotide is indicated in red.
|Illustration of Mutations in
Gene & Protein
Jak3 encodes Janus kinase 3 (JAK3). JAK3 has seven different highly conserved JAK homology (JH) regions (JH1-JH7) [Figure 6; reviewed in (1)]. The JH1 region is the kinase domain (amino acids 818-1091), the JH2 domain corresponds to the pseudokinase domain (amino acids 517-773), the JH3 and JH4 regions comprise an Src Homology 2 (SH2)-like domain (amino acids 370-460), and the JH6 and JH7 regions consist of a 4.1, ezrin, radixin, moesin (FERM) homology domain (alternatively, B41 domain; amino acids 20-254). The citron mutation is predicted to result in deletion of exon 22 which encodes amino acids 990-1023 within the JAK3 kinase domain, a frame-shift, and coding of a premature stop codon within the JAK3 kinase domain. Expression and localization of JAK3citron have not been examined.
Please see the record mount_tai for more information about Jak3.
JAK3 binding is restricted to hematopoietic-specific cytokine receptors that have a γc receptor subunit (i.e., the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors) [reviewed in (1)]. The γc receptor-associated cytokines have known functions. For example, IL-7 is necessary for T and B cell development, IL-2 functions in peripheral T cell homeostasis and antigen-driven T-cell expansion, IL-15 functions in natural killer (NK) cell differentiation, IL-4 functions in B-cell maturation and isotype switching (2). JAK3 mutations result in defective γc receptor-associated signaling and subsequent defects in lymphocyte development (2;3). Mutations in JAK3 are linked to autosomal recessive T- and NK-cell negative/B-cell positive type of severe combined immunodeficiency [T−B+NK- SCID; OMIM: #600802; (4-6); reviewed in (2)]. Patients with T−B+NK- SCID do not have T or NK cells, but have normal to elevated numbers of immature nonfunctional B lymphocytes (5;6). Patients with SCID have persistent, recurring infections due to loss of T cell-associated immunity. Jak3 knockout (Jak3-/-) mice have reduced numbers of T, B, γδ T, and NK cells (7-11). B cell maturation in the Jak3-/- mice is blocked at the pre-B stage, leading to a reduced frequency of IgM+ B cells (10). In contrast to Jak3-/- mice, citron mice exhibit increased frequencies of IgM+ B cells. Similar to patients with T−B+NK- SCID, the citron mice have increased frequencies of peripheral B cells, including the IgM+ and IgD+ B cells; however the frequency of peripheral T and NK cells were comparable between the citron and wild-type mice, indicating that JAK3citron may retain some function.
1) 94°C 2:00
The following sequence of 665 nucleotides is amplified (chromosome 8, + strand):
1 gccatacttc acattgacga ctccctcccc aggccactgt ttcacaccct gcccactctc
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Wu, W., and Sun, X. H. (2012) Janus Kinase 3: The Controller and the Controlled. Acta Biochim Biophys Sin (Shanghai). 44, 187-196.
2. Notarangelo, L. D., Mella, P., Jones, A., de Saint Basile, G., Savoldi, G., Cranston, T., Vihinen, M., and Schumacher, R. F. (2001) Mutations in Severe Combined Immune Deficiency (SCID) due to JAK3 Deficiency. Hum Mutat. 18, 255-263.
3. Thomis, D. C., and Berg, L. J. (1997) The Role of Jak3 in Lymphoid Development, Activation, and Signaling. Curr Opin Immunol. 9, 541-547.
4. Candotti, F., Oakes, S. A., Johnston, J. A., Giliani, S., Schumacher, R. F., Mella, P., Fiorini, M., Ugazio, A. G., Badolato, R., Notarangelo, L. D., Bozzi, F., Macchi, P., Strina, D., Vezzoni, P., Blaese, R. M., O'Shea, J. J., and Villa, A. (1997) Structural and Functional Basis for JAK3-Deficient Severe Combined Immunodeficiency. Blood. 90, 3996-4003.
5. Macchi, P., Villa, A., Giliani, S., Sacco, M. G., Frattini, A., Porta, F., Ugazio, A. G., Johnston, J. A., Candotti, F., and O'Shea, J. J. (1995) Mutations of Jak-3 Gene in Patients with Autosomal Severe Combined Immune Deficiency (SCID). Nature. 377, 65-68.
6. Russell, S. M., Tayebi, N., Nakajima, H., Riedy, M. C., Roberts, J. L., Aman, M. J., Migone, T. S., Noguchi, M., Markert, M. L., Buckley, R. H., O'Shea, J. J., and Leonard, W. J. (1995) Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development. Science. 270, 797-800.
7. Nosaka, T., van Deursen, J. M., Tripp, R. A., Thierfelder, W. E., Witthuhn, B. A., McMickle, A. P., Doherty, P. C., Grosveld, G. C., and Ihle, J. N. (1995) Defective Lymphoid Development in Mice Lacking Jak3. Science. 270, 800-802.
8. Park, S. Y., Saijo, K., Takahashi, T., Osawa, M., Arase, H., Hirayama, N., Miyake, K., Nakauchi, H., Shirasawa, T., and Saito, T. (1995) Developmental Defects of Lymphoid Cells in Jak3 Kinase-Deficient Mice. Immunity. 3, 771-782.
9. Baird, A. M., Thomis, D. C., and Berg, L. J. (1998) T Cell Development and Activation in Jak3-Deficient Mice. J Leukoc Biol. 63, 669-677.
10. Thomis, D. C., Gurniak, C. B., Tivol, E., Sharpe, A. H., and Berg, L. J. (1995) Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3. Science. 270, 794-797.
|Science Writers||Anne Murray|
|Authors||Ming Zeng, Kuan-Wen Wang, Jin Huk Choi, Bruce Beutler|